Preclinical data show intracellular uptake of a ligand-siRNA conjugate in vitro using megalin, an endogenous, endocytic recycling receptor on proximal tubular cells of the kidney
Megalin-mediated delivery of siRNA leads to significant, durable knock-down in vivo
CAMBRIDGE, Mass.--(BUSINESS WIRE)--Judo Bio, a biotechnology company pioneering oligonucleotide medicines delivered to the kidney, today announced the presentation of preclinical data that demonstrate a mechanism of uptake and trafficking of ligand-siRNA conjugates using megalin receptors to achieve targeted gene knockdown in proximal tubule epithelial cells (PTEC) of the kidney. The data is being presented at Kidney Week 2024, the annual meeting of the American Society of Nephrology, taking place in San Diego, CA on October 24-27.
These data represent the capabilities of the Company’s STRIKE (Selectively Targeting RNA Into KidnEy) platform to discover ligand‑siRNA conjugates that harness the natural, endogenous process of receptor-mediated endocytosis to deliver oligonucleotide therapeutics to specific kidney cell populations. Megalin-STRIKERs are ligand-siRNA conjugates that bind to megalin on PTECs, resulting in drug uptake to the kidney and gene silencing of the target mRNA. In its initial drug programs, Judo Bio is designing megalin-STRIKERs to silence mRNA expression of specific solute carrier (SLC) proteins, thereby inhibiting the uptake of circulating metabolites linked to systemic diseases.
“Our understanding of endocytic trafficking in kidney proximal tubule cells has advanced rapidly in recent years,” said Ora A. Weisz, PhD, an author of the poster presentation and Professor of Medicine, Cell Biology, and Clinical and Translational Science in the Division of Renal-Electrolyte at the University of Pittsburgh. “This approach to harness the endocytic pathway to selectively target delivery of RNA to specific kidney cells provides an opportunity to target and silence solute carrier proteins in order to address numerous systemic diseases.”
The preclinical data presented at Kidney Week studied megalin ligand-conjugated siRNA, or megalin-STRIKERs, in a differentiated, opossum kidney PTEC cell line that recapitulates proximal tubule morphology and is functionally similar to kidneys in animals. Key findings include:
- Ligand-siRNAs were taken up by opossum kidney cells in both a time and concentration dependent manner, predominantly from the apical surface.
- Uptake of ligand-siRNA conjugates was megalin dependent and achieved with different megalin ligands.
- Megalin ligand-siRNA conjugates led to significant gene knock-down across multiple targets and was durable for up to 40 days in mice.
Judo Bio’s Kidney Week poster presentation is available here on the company’s website.
“We are pleased to share data describing the use of megalin’s endogenous receptor-mediated endocytosis to enable gene silencing in PTECs,” said Alfica Sehgal, PhD, Chief Scientific Officer of Judo Bio. “Understanding the mechanism that leads to gene silencing directs the optimization efforts on our first megalin-STRIKERs that target SLC proteins. Modulating function of specific SLCs is an established approach for the treatment of various systemic diseases, and an RNAi approach opens vast therapeutic opportunities because of its specificity.”
About Judo Bio
Judo Bio is pioneering oligonucleotide medicines delivered to the kidney, opening the way for new genetic medicines for systemic and renal diseases. With its STRIKE (Selectively Targeting RNA Into KidnEy) platform, the company is using a proprietary approach to create ligand-RNA conjugate drugs designed for receptor-mediated update by specific kidney cell types, resulting in gene silencing of disease-modifying target genes. Judo Bio’s initial pipeline programs are megalin-STRIKERs that use the megalin receptor family to selectively deliver siRNA therapeutics to the proximal tubule of the kidney to silence mRNA expression of specific solute carrier proteins (SLCs), thereby inhibiting the uptake of circulating solutes linked to systemic diseases. Located in Cambridge, MA, Judo Bio’s team and advisors include experts in oligonucleotide therapies and innovative drug development. For more information, visit www.judo.bio and follow us on LinkedIn.
Contacts
Media:
Kathryn Morris
The Yates Network LLC
914-204-6412
kathryn@theyatesnetwork.com
